Cardiovascular actions of ET-B activation in vivo and modulation by receptor antagonism.
The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and participates in vasodilatation and vasoconstriction. Controversy exists regarding the role of the ET-B receptor as a mediator of systemic, pulmonary, and renal vasoconstriction in states of marked ET-1 activation. Moreover, the potential activation of endogenous ET-1 with secondary stimulation of the ET-A receptor in response to sarafotoxin S6c (S6c) remains unclear. This study was designed to assess the cardiovascular actions of ET-B activation with S6c in the presence and absence of selective ET-A antagonism with FR-139317 and dual ET-A/ET-B antagonism with SB-209670 in the anesthetized dog. Compared with time control (n = 5), S6c increased from baseline systemic vascular resistance (SVR) [28 +/- 7 vs. 14 +/- 3 resistance units (RU), P < 0.05] and pulmonary vascular resistance (PVR) (3.2 +/- 0.7 vs. 0.9 +/- 0.3 RU, P < 0.05) and decreased cardiac output (CO) (-1.7 +/- 0.3 vs. -0.5 +/- 0.1 l/min, P < 0.05), with no differences in renal vascular resistance in association with increases in plasma ET-1. S6c also decreased mixed venous oxygen saturation (SVO2) (56 +/- 6 vs. 76 +/- 5%, P < 0.05). Selective ET-A receptor antagonism did not affect the actions of S6c, with the exception that ET-A receptor antagonism blocked the increase in SVR to high-dose S6c. Dual ET-A/ET-B receptor antagonism attenuated the increase from baseline in SVR (7 +/- 1 vs. 28 +/- 7 RU, P < 0.05) and PVR (0.7 +/- 0.2 vs. 3.2 +/- 0.7 RU, P < 0.05) and decrease from baseline in CO (-0.9 +/- 0.1 vs. -1.7 +/- 0.3 l/min, P < 0.05) and SVO2 (-7 +/- 3 vs. -20 +/- 3%, P < 0.05) observed with S6c alone. In summary, this study demonstrates an important role of ET-B receptor activation in vivo, which results in increases in plasma ET-1 and systemic and pulmonary vasoconstriction and reductions in CO and SVO2. This study also supports a modest role for the ET-A receptor in mediating the systemic vasoconstrictor response to high-dose S6c.
Rasmussen
T E
TE
Division of Cardiovascular Disease, Mayo Clinic, Rochester, Minnesota 55905, USA.
Jougasaki
M
M
Supaporn
T
T
Hallett
J W
JW
Brooks
D P
DP
Burnett
J C
JC
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D006706:Homeostasis; D011652:Pulmonary Circulation / Q000187:drug effects; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D012079:Renal Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014757:Viper Venoms / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6